**2. Drug treatment options available for Covid-19 treatment and management**

#### **2.1 Drug treatment for Mild to moderate Covid-19 infection**

#### *2.1.1 Molnupiravir*

Molnupiravir is an orally accessible prodrug of the nucleoside analogue -D-N4 hydroxycytidine and is a broad-spectrum antiviral (NHC). In replicating coronaviruses, molnupiravir or NHC can promote G to A and C to U transition mutations [14].

*Mechanism of action*: NHC circulates systemically after molnupiravir dosing and is phosphorylated intracellularly to NHC triphosphate. Viral RNA polymerase incorporates NHC triphosphate into viral RNA, which then misdirects viral polymerase to incorporate either guanosine or adenosine during viral replication. As a result, detrimental mistakes accumulate throughout the viral genome, rendering the virus non-infectious and unable to replicate [15].

*Adverse effects*: Diarrhea, Dizziness and Nausea [16]. *Other indications*: NA.

#### *2.1.2 Azithromycin*

Azithromycin is a broad-spectrum macrolide antibiotic with a protracted halfexistence and tremendous tissue penetration. It is mostly used for the remedy of respiration, enteric and genitourinary infections and can be utilized in desire to different macrolides for a few sexually transmitted and enteric infections. Azithromycin has extra immunomodulatory consequences and has been utilized in continual respiration inflammatory illnesses for this purpose [17].

*Mechanism of action*: Azithromycin has antiviral action against SARS-CoV-2 and may act at various stages of the viral cycle. Its immunomodulatory features include the capacity to reduce cytokine production, maintain epithelial cell integrity, and prevent fibrosis in the lungs [18].

*Adverse effects*: QTc prolongation has been linked to torsade's de pointes and polymorphic ventricular tachycardia, rarely hepatotoxicity [18].

*Other indications*: Community-acquired pneumonia, in relation to its activity against Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. Treatment of other upper respiratory diseases, like acute otitis media and acute reoccurrence of chronic obstructive pulmonary disease [19].

*Inclusive Review on Existing Treatment and Management Modalities for COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.106011*

#### *2.1.3 Favipiravir*

Favipiravir is an oral medication that was authorized in Japan in 2014 for new and re-emerging pandemic influenza. Favipiravir (prodrug) is a purine base analogue that undergoes intracellular phosphoribosylation to become active favipiravir ribofuranosyl-5B triphosphate (favipiravir-RTP).

*Mechanism of action*: Favipiravir is integrated into the nascent viral RNA via the errorprone viral RdRp, resulting in viral mutagenesis and chain termination. The presence of RdRp in many types of RNA viruses allows favipiravir to have a broader spectrum of antiviral activity. Favipiravir-RTP acts as a mutagen after RNA viral inclusion, allowing it to avoid coronavirus repair machinery. Overall, favipiravir-RTP has a beneficial effect on SARS-CoV-2 by inducing a cytopathic effect, which reduces the number of viral RNA and infectious particles, as well as increasing the frequency of mutation [20].

*Adverse effects*: Abnormal liver function tests, psychiatric symptom reactions, digestive tract reactions and raised serum uric acid [3].

*Other indications*: RNA viruses such as resistant influenzas virus, arenaviruses, Bunyaviruses, floviruses, Rift Valley Fever, Yellow Fever, West Nile, Western equine encephalitis, foot-and-mouth disease virus, norovirus and avian influenza [3].

#### *2.1.4 JAK-STAT inhibitors*

As cytokines are clearly important in the fight against viral infections, the hyperinflammatory conditions caused by the SARS-CoV-2 infection due to the cytokine storm.

*Mechanism of action*: STAT proteins with SH2 domains are inactive and restricted to the cytoplasm in unstimulated cells. STAT proteins use SH2 domains to bind to the phospho-tyrosine that includes receptor sequences after cytokine receptor stimulation. Furthermore, JAK-induced phosphorylation of STAT proteins at cytokine type receptors results in STAT protein dimerization. STATs can translocate inside the nucleus and trigger apoptosis, immunological modulation, cell cycle differentiation, and gene transcription due to their dimerization.

*Adverse effects*: Ruxolitinib: Purpuric lesions on the skin of limbs and erythrodermic rashes in 2 SARS-CoV-2 patients.

*Long term use of Baricitinib*: Serious infections and thromboembolic events in patients.

*Tofacitinib*: Abdominal pain, acne vulgaris, anemia, angioedema, diarrhea, dehydration, dyspepsia, headache, hepatotoxicity, hyperlipidemia, hepatitis, lymphoma, lymphopenia, nausea, neutropenia, pulmonary embolism, rashes, vomiting, blood clots, GI perforations [21].

*Other indications*: Rheumatoid arthritis, Psoriatic arthritis, Ulcerative Colitis, Chron's disease, Alopecia areata, Vitiligo, Psoriasis, Atopic dermatitis [22].

#### **2.2 Drug treatment for severe Covid-19 infection**

#### *2.2.1 Remdesivir*

Remdesivir (RDV), also known as GS-5734, is a monophosphoramidate prodrug and adenosine nucleoside analogue that is converted to GS-441524, the active form [3].

*Mechanism of action*: Remdesivir inhibits viral RNA-dependent RNA polymerase (RdRp), which is involved in viral genome replication. When remdesivir is metabolized by the host cells into its pharmacologic active analogue, adenosine triphosphate (GS-443902), it competes with ATP for integration by the RdRp complex into the nascent RNA strand, resulting in the cessation of RNA synthesis and reducing viral replication [23].

*Adverse effects*: Hypotension, arrhythmias, and cardiac arrest, Dyspnea, Acute respiratory failure, acute respiratory distress, pneumothorax, pulmonary embolism, Anemia, lymphopenia, Hyperglycemia, Pneumonia, septic shock, Elevated lipase, nausea, vomiting, diarrhea, constipation, poor appetite, gastroparesis, and lower GI bleeding, Acute kidney injury or worsening of underlying chronic kidney disease, hypernatremia, hypokalemia, Headache, lightheadedness, Rash, contact dermatitis, pruritus, Delirium, Pyrexia, insomnia, multi-organ dysfunction and DVT.

*Other indication*: Ebola Virus [24].

#### *2.2.2 Dexamethasone*

Dexamethasone is a corticosteroid with anti-inflammatory and immunosuppressive properties that is used to treat a variety of illnesses [25].

*Mechanism of action*: It works by blockade of inflammation pathways, vasodilation and immune cell migration [26].

*Adverse effects*: Hyperglycemia, secondary infections, psychiatric effects, avascular necrosis [25].

*Other indications*: Allergic states, GIT disorders, Hematologic disorder, Renal disorders [25].

#### *2.2.3 Selinexor*

Selinexor, a selective inhibitor of nuclear localization compound that structures exportin 1 (XPO1) and compels nuclear concentration and initiation of oncogenic proteins, inhibits transcription factor nf B, and reduces oncoprotein messenger RNA translation, could be a new treatment option for myeloma that has resisted current treatments [27].

*Mechanism of action*: The severe pulmonary inflammation associated with COVID-19, as well as high levels of cytokines such as IL6, IL1, IFNg, and others, is one of the most essential features of the virus. Selinexor has shown substantial anti-inflammatory effect by inhibiting Nuclear Factor kB (NF-kB), resulting in decreases in all of these cytokines and is helpful especially for COVID-19 patients who are hospitalized [28].

*Adverse effects*: Blurred vision, Cataract was reported as the most widespread side effect [29]. Nausea, vomiting, diarrhea, constipation, weight loss. Loss of appetite. Extreme tiredness. Difficulty falling asleep or staying asleep. Headache. taste changes. Easy bleeding or bruising, fatigue, pale skin, or shortness of breath, fever, cough, chills, or other signs of infection, seeing things or hearing voices that do not exist, confusion, double vision and increased sensitivity to light and glare [30].

*Other indications*: Selinexor is indicated for the remedy of relapsed or refractory a couple of myelomas in aggregate with dexamethasone. Patients need to have acquired as a minimum four previous treatments and feature sickness that's refractory to least proteasome inhibitors, as a minimum immunomodulatory agent, and an anti-CD38 monoclonal antibody [31].

#### *2.2.4 Nitric oxide*

In the cardiovascular and immune systems, nitric oxide plays a significant pathophysiological role. NO works as a selective pulmonary vasodilator to promote oxygenation and lessen pulmonary vascular resistance [32].

#### *Inclusive Review on Existing Treatment and Management Modalities for COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.106011*

*Mechanism of action*: NO has the ability to act as a vasodilator and immunological regulator. As a vasodilator, it works as a selective pulmonary vasodilator to improve oxygenation and reduce pulmonary vascular resistance, as a bronchial/airway dilator to promote oxygen inhalation, as a vascular anticoagulant to prevent blood clotting and excessive platelet activation [33].

*Adverse effects*: Blurred vision, dizziness, faintness, or light-headedness. Sweating, Unusual exhaustion or weakness. Incidence not known: bluish lips or skin, Chest discomfort, Difficult or labored breathing, Dizziness, Tightness in the chest, Trouble breathing [33]. Clinical adverse effects of iNO include the following: Worsening heart failure, Hypotension, Pulmonary vasospasm, Methemoglobinemia [34, 35].

*Other indications*: Pulmonary Hypertension in Infants, Chronic Lung Disease in the Infant [34]. Improve oxygenation and reduce the risk of extracorporeal membrane oxygenation in term and near-term infants with hypoxic respiratory failure and clinical and/or echocardiographic signs of pulmonary hypertension [35].

#### *2.2.5 Paxlovid*

Ritonavir-Boosted Nirmatrelvir. Nirmatrelvir is an orally absorbed protease inhibitor that inhibits MPRO, a viral protease that cleaves the two viral polyproteins required for viral replication. It has shown antiviral activity against all known coronaviruses that infect people [36].

*Mechanism of action*: Paxlovid is made up of two drugs: nirmatrelvir, which stops the virus from replicating by inhibiting a SARS-CoV-2 protein, and ritonavir, which slows down the breakdown of nirmatrelvir and allows it to stay in the body for longer at higher concentrations [37].

*Adverse effects*: Diarrhea, Altered or impaired sense of taste, Muscle aches, Increased blood pressure [38].

#### **2.3 Supportive treatments for Covid-19 infection**

#### *2.3.1 Paracetamol*

Paracetamol, often known as acetaminophen, is a pain reliever and fever reducer commonly used for mild to moderate pain and discomfort. This medicine has been prescribed to alleviate the symptoms of COVID-19 infection, which include fever, body aches, and headaches. Patients with these symptoms may find relief with paracetamol, but it is not a treatment for COVID-19 [39].

*Adverse effects*: Itchy, red, swollen, blistered, or peeling skin, wheezing, chest or throat tightness, difficulty breathing or speaking, swelling of the mouth, face, lips, tongue, or throat [40].

#### *2.3.2 Vitamin D*

It has the ability to function autocrinally in a local immunologic environment. Vitamin D has the ability to influence both innate and adaptive immune responses. Vitamin D deficiency has been linked to increased autoimmunity and susceptibility to infection. As immune cells in autoimmune diseases are responsive to the ameliorative effects of vitamin D, the beneficial effects of supplementing vitamin D-deficient individuals with autoimmune disease may extend beyond the effects on bone and calcium homeostasis [41].

*Mechanism of action*: Vitamin D receptors are found on B cells, T cells, and antigenpresenting cells, among other immune cells. Because these cells may generate the active vitamin D metabolite, vitamin D has the potential to manipulate innate and adaptive immune responses [42].

*Adverse effects*: Some side effects of taking too much vitamin D include weakness, dry mouth, nausea, vomiting, and others. Taking vitamin D for long periods of time in doses higher than 4000 IU (100 mcg) daily is possibly unsafe and may cause very high levels of calcium in the blood [43].

*Other indications*: Osteoporosis, Hypoparathyroidism, Vitamin D resistant Rickets, Familial Hypophosphatemia [44].

#### *2.3.3 Vitamin C*

Vitamin C levels in serum and leukocytes are depleted during the acute stage of infection owing to increased metabolic demands. Vitamin C supplementation at a high dose aid in the normalization of serum and leukocyte vitamin C levels. Vitamin C has a number of pharmacological properties, including antiviral, anti-oxidant, antiinflammatory, and immunomodulatory activities, making it a promising treatment choice for COVID-19 [45].

*Mechanism of action*: Vitamin C, also known as ascorbic acid, is a water-soluble nutrient that is vital for human health. Immune responses rely heavily on ascorbic acid. As an antioxidant, vitamin C plays a vital homeostatic role. It has been shown to have direct virucidal activity as well as increase interferon production. Both the innate and adaptive immune systems have effector mechanisms. Vitamin C inhibits NF-B activation, which reduces reactive oxidative species (ROS) and inflammation. While SARS-CoV-2 suppresses the expression of type-1 interferons (the host's main antiviral defense), ascorbic acid increases the expression of these important host defense proteins [46].

*Adverse effects*: Nausea, vomiting and diarrhea, Heartburn, Stomach cramps or bloating, Fatigue and sleepiness, or sometimes insomnia, Headache, Skin flushing. Vitamin C supplements taken orally, especially in large doses, might produce kidney stones. The use of oral vitamin C supplements in excess of 2000 milligrams per day for an extended period of time raises the risk of serious side effects [47].

*Other indication*: Assisting in the protection and maintenance of cells. Maintaining healthy skin, blood vessels, bones and cartilage. Assisting in the healing of wounds [48].

#### *2.3.4 Zinc*

Zinc is a trace mineral, which means it is only needed in minute amounts by the body, yet it is required for almost 100 enzymes to carry out critical chemical reactions. It plays an important role in the formation of DNA, cell development, protein synthesis, tissue repair, and immune system support [49].

*Mechanism of action*: Zn supplementation has the ability to increase innate and humoral antiviral immunity, as well as restore reduced immune cell activity or improve normal immune cell function, especially in immunocompromised or elderly patients. When used with normal antiviral therapy, Zn has been shown to have a synergistic effect in patients with hepatitis C, HIV, and SARS-CoV-1. Physical processes such as virus adhesion, infection, and uncoating are primarily responsible for Zn′s effectiveness against a variety of viral species. Zn may also protect or stabilize the cell membrane, which may help to prevent the virus from entering the cell [50].

*Inclusive Review on Existing Treatment and Management Modalities for COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.106011*

*Adverse effects*: Indigestion, Diarrhea, Headache, Nausea, Vomiting [51].

*Other indications*: Zinc can be used to treat zinc deficiency, diarrhea, and Wilson disease. Acne, diabetes, anorexia, burns, and a variety of other conditions are all treated with zinc. Several scientific evidence supports its usage in the treatment of some of these conditions [52].

Additionally, supplemental oxygen therapy is provided to patients with Severe Covid and respiratory distress, hypoxemia, or shock. Oxygen therapy at 5 L/ min and titrate flow rates to reach target SpO2 ≥ 90% in non-pregnant adults and SpO2 ≥ 92–96% in pregnant patients. NIV/HFNC (Helmet or face mask interface depending on availability) should be used in patients with increasing oxygen requirement, if work of breathing is increasing.

Intubation should be prioritized in patients with high work of breathing /if NIV is not tolerated., presence of hemodynamic instability, altered mental status or multiorgan failure. Ventilatory management carried out according to protocol [53].
